Overall health depends on mitochondrial health. Virtually all health conditions from physical and mental performance to cardiovascular health and aging are impacted by mitochondrial health. Optimizing it is therefore a powerful strategy to extend one’s healthspan, or longer quality of life.
Mitochondria are the powerhouse of the cell. They produce and release energy in the citric acid (krebs) cycle and the Electron Transport Chain (ETC).
Mitochondria are essential to cellular function. Cells cannot function without them. Mitochondrial dysfunction is implicated in diabetes, cardiovascular disease, stroke, concussion, and most neurodegenerative diseases. [Chistiakov][Jang]
Measuring Mitochondrial Health
As of 2021, health practitioners can’t test mitochondrial health, so they ignore it.
Commonly performed tests are inadequate. However, changes in overall health can be observed through better tests. Although these better tests don’t provide direct feedback on mitochondrial health, they do provide a more accurate representation of total health than the commonly prescribed, sometimes misleading tests.
Specifically requested performance tests can measure these values through indirect means. Tests such as blood glucose, kidney function, blood pressure, VO₂ max, and cardio IQ can give a rough indication of overall mitochondrial health.
Healthcare Diagnostic Failings
How Doctors Test Your Kidneys
Doctors assess kidney function by glomerular filtration rate (GFR), typically by an eGFR test. eGFR measures blood creatinine — that’s it — and uses fudge factor adjustments that include age, gender, race, and weight, as WebMD officiously explains. They use bodyweight to determine how much muscle you have (WRONG). The thinking behind this is that people have roughly the same ratio of lean body mass to adipose tissue (fat) (WRONG) and, since greater muscle mass leads to greater creatinine levels, heavier people must have more muscle (WRONG). Thus, heavier people with a higher GFR can be expected to be in good health (WRONG).
The eGFR test, which is practically useless for assessing kidney function, is a normal example of healthcare-industry turd-polishing. Be aware of this type of erroneous thinking, established into practice, look out for other such errors, and ask questions and seek answers.
Exercise increases creatinine, a metabolic waste product. And, since exercise increases liver enzymes, increased exercise might also indicate to your doctor that your kidneys and liver are in worse shape — more evidence to him that your new fad health regimen is just more quackery. And, if you’re also taking creatine monohydrate, that will also increase creatinine levels, leading to lower eGFR score, crudely indicating to your assumptive doctor that your kidneys and liver are in worse shape. Your doctor might even tell you to stop taking or doing whatever it is you are doing. Keep in mind, you own your health; your doctor is there to serve you. If you can’t get him to do that, find another doctor.
A better test of kidney function is a Creatinine Clearance test and an albumin/creatinine ratio test. These test circulating creatinine, urinary creatinine, and urinary albumin. Doctors don’t generally request these tests. If you want them, you’ll have to ask for them.
How Doctors Test Your Cardiovascular Health
Low Density Lipoprotein (LDL) particle number assessment is another widespread failing of modern health care. Calculating LDL-C is expensive for widespread screening so, as it is with kidney function, modern healthcare doesn’t test what they find to be “too expensive” and again performs a rough guesstimate.
The alternative to the widespread failure of lipid panel guesstimation is NMR spectronomy particle testing, such as Cardio IQ, which actually measures LDL levels, as well as their size and shape.
Heart disease is the #1 killer in the US, costing an estimated $363 billion dollars per year. That, however, has not stopped the healthcare industry from saving a few bucks by sticking to tradition and avoiding the slightly more expensive NMR tests which have been decreasing in cost over the past thirty years.
Although the best healthcare diagnostics are generally crude, improvements are being made. Get your doctor to work for you. DYOR, find the lab tests you want, communicate with your doctor, and listen to your body.
How Mitochondrial Health and Function can be Improved
On a cellular level, mitochondrial function can be improved in a few ways.
- Mitochondrial biogenesis
- Increased mitochondrial activity
- Mitochondrial strength
- Mitochondrial protection
There are several things you can do to affect those parameters. Understanding of their pathways is key to understanding what, why and how things work.
AMPK and PGC-1 alpha
The AMPK/PGC-1 alpha pathway leads to mitochondrial biogenesis and health.
PGC-1 alpha, the “master regulator” of mitochondrial biogenesis, regulates cellular energy metabolism and induces mitochondrial biogenesis. PGC-1a stands for PPAR Gamma Coactivator-1 alpha. PPAR’s regulate gene expression and PGC 1-a is a PPAR co-activator that regulates cellular energy metabolism. [Liang]
PGC-1 alpha can be activated by a number of things mentioned in this article. Anything that increases PGC-1a increases mitochondrial strength, number, and function.
Anything that increases AMPK increases PGC-1α. [Cantó], though AMPK does more than increase PGC 1-a.
AMPK or AMP-Activated Protein Kinase, is an enzyme that catalyzes the transfer of AMP to ADP to form ATP. ATP is a form of stored energy that is released in the citric acid cycle, forming ADP and AMP. When AMP/ATP or ADP/ATP ratios are too high, AMPK is increased. Increases in AMPK activation and PGC-1a lead to increases in mitochondrial DNA and mitochondrial strength and number.
Lance Hitchins does a deep dive into AMPK
NAD+ — Mitochondrial Fuel
Nicotinamide Adenine Dinucleotide (NAD+) is used in ATP production in the ETC. Think of NAD+ as fuel for mitochondria.
Synergy: Do Everything
Results come from consistent, total application. A halfway applied program leads to partial results. Most people will apply a small fraction of what little they understand and achieve a poor result. Although I explain what to do (exercise, supplements, peptides, etc), it’s up to you to do it consistently. And I’ve explained why and how, so that it can be understood, not followed on blind faith.
Exercise
Physical exercise is the best way to improve mitochondrial health and will have the greatest observable effects on overall health. Exercise should be at the core of any program. Exercise is the best way to increase AMPK.
Exercise increases PGC-1 alpha which stimulates mitochondrial biogenesis. Exercise also causes release of mitochondrial-derived peptides such as MOTS-c, a naturally-produced (more on MOTS-c below). Exercise strengthens mitochondria in all 3 muscle (skeletal, cardiac, and smooth) types, organs like the liver and kidney, and even nervous tissues of the brain. [Park][Steiner]
The most effective type of exercise for improving mitochondrial health is generally agreed to be high-intensity cardiovascular training at or above 75% maximal power (such as high intensity interval training (HIIT)). This is because PGC-1α expression at both the mRNA and protein level increases in an exercise intensity-dependent manner. Supplements, peptides, other approaches to improve performance can raise individual limits of beneficial HIIT. However, a conditioned response to HIIT decreases in benefit after more than 40 repeated bouts. [Bishop][Granata]
Intermittent Fasting
Intermittent Fasting (IF) is fasting between 12 to 24 hours. Several studies have reported significant reductions in body weight and fat mass with no significant changes in lean mass.
Fasting, like exercise, raises PGC-1 alpha. Intermittent fasting (IF) combined with high intensity interval training has synergistic effects suggesting increased mitochondrial mass. [Real-Hohn]
Cold Temperature
Cold exposure strongly induces a release of PGC-1 alpha and, as a result, induces mitochondrial biogenesis. [Chung]
Red Light Therapy, Photobiomodulation (PBM)
The wavelengths 660nm and 850nm increase ATP, increase mitochondrial membrane potential (for the ETC), and improve mitochondrial function in brain, muscle, eye, and organ tissues and, when used pre-workout, reduces post-workout creatine kinase levels. [Silveira][Eells][Keszler][Leal-Junior]
“[Photobiomodulation’s] principal player is the mitochondrion, whether its cytochromes are directly involved as a photoacceptor or indirectly through a vibrational and energetic variation of bound water: water as the photoacceptor.” [Ravera]
Whole body near-infrared (NIR) and IR before exercise increases mitochondrial membrane potential and ATP synthesis with a peak response at 3-6 hours. [Ferraresi]
Follow the instructions recommended by the device manufacturer, usually 20 minutes per day.
Fasted Training Strategy
Sleep early, rise early, do red light therapy for 15–20 minutes, train hard fasted, and then follow with cold or contrast hot/cold showers.
Mitochondrial Peptides Stack
| Peptide | Dose |
|---|---|
| 5-Amino-1MQ | 50mg daily for two months |
| Prevents breakdown of NAD+. | |
| MOTS-c | 5mg EOD for two to three weeks |
| Increases PGC-1α expression, attenuates insulin resistance, and enhances glucose metabolism via the AMPK signaling pathway. [Yang] | |
| SS-31 | 0.5mg / kg bodyweight EOD for two to three weeks |
| Strengthens the cristae, the structures of the inner mitochondria where the ETC takes place. Reduces free radical production, improves exercise tolerance, and improves diseases stemming from mitochondrial dysfunction. [Campbell][Siegel] | |
Mitochondrial Supplement Stack
| Substance | Dose |
|---|---|
| NMN | 500–1000mg daily |
| Increases NAD for energy in the electron transport chain (ETC). | |
| PQQ | 50–150mg daily |
| Stimulates mitochondrial biogenesis. Protects against exercise-induced fatigue and oxidative damage by improving mitochondrial function. | |
| CoQ₁₀ Ubiquinol or Phytosome Q10 (Ubiqsome) | 300-500mg daily |
| Generates ATP from metabolic products in the ETC. Protects mitochondria from oxidative damage and dysfunction. | |
| r-ALA | 100mg with larger meals |
| Reduces mitochondrial dysfunction and oxidative damage. Induces mitochondrial biogenesis. Complementarily promotes mitochondrial synthesis with ALCAR. Restores insulin sensitivity in muscle cells. [Shay] | |
| ALCAR | 500 – 1000mg pre workout or w/ carbs, 1-2x daily |
| Nutritively shuttles activated long chain fatty acids into the mitochondria (“carnitine shuttle”). Restores mitochondrial function and increases mtDNA. | |
| Creatine | 5-10g daily, w/ carbs |
| Increases ATP used in the krebs cycle. Prevents mitochondrial damage, increases mtDNA, and induces mitochondrial biogenesis. | |
| Coleus Forskolin | With large meals |
| Activates cAMP pathway for mitochondrial biogenesis, increased mtDNA, and mitochondrial activity. | |
| Citicoline (CDP Choline) | 1000mg prior to exercise |
| Strengthens mitochondrial membranes. [Rao] | |
Mitochondrial Peptides Detail
5-Amino-1MQ
5-Amino-1MQ inhibits nicotinamide N-methyltransferase (NNMT). NNMT is an enzyme that breaks down NAD+. Thus, inhibiting NNMT causes an increase in NAD+.
5-Amino-1MQ also activates senescent muscle stem cells, increases muscle recovery, and increase metabolism. [Neelakantan 1]
5-Amino-1MQ inhibits nicotinamide N-methyltransferase (NNMT). NNMT is an enzyme that breaks down NAD+. Thus, inhibiting NNMT causes an increase in NAD+.
5-Amino-1MQ has been shown to activate senescent muscle stem cells, and improve regenerative capacity of aged skeletal muscle, and increase metabolism. [Neelakantan 1][Neelakantan 2] [Neelakantan 1][Neelakantan 2]
MOTS-c
Mitochondrial Open reading frame (ORF) of the twelve S-c (MOTS-c) is a mitochondrially-derived peptide that responds to physical activity. MOTS-c regulates insulin sensitivity, physical capacity and performance.
MOTS-c is a peptide that improves physical function, insulin sensitivity, and metabolic disease states. MOTS-c is produced naturally in humans and is synthesized and sold as a peptide for research purposes.
Exogenous MOTS-c, combined with exercise, synergistically upregulates PGC-1α expression, attenuates insulin resistance, and enhances glucose metabolism via the AMPK signaling pathway. [Yang]
SS-31
SS-31 is a peptide found in the inner membrane of mitochondria, an area where free radicals are produced. SS-31 strengthens the cristae, the structures of the inner mitochondria where the ETC takes place.
Because SS-31 strengthens the inner mitochondria, it reduces free radical production, improves exercise tolerance, and improves diseases stemming from mitochondrial dysfunction. [Campbell][Siegel]
SS-31 restores healthy mitochondrial function, thus, it is primarily of benefit to aged individuals undergoing intense exercise training or those fighting T2D, Parkinson’s, or Alzheimer’s diseases. SS-31 has no effect on young, healthy mitochondria.
In 2021 study out of the University of Washington, researchers found NMN and SS-31 effective at restoring different aspects of mitochondrial and heart health, each through its own respective mechanisms. Combining the two resulted in a synergistic effect that rejuvenated old hearts to the young state. [Whitson]
SS-31 is also an orphaned drug, so, due to government control, it is not readily available for purchase.
These peptides can and should be synergistically complemented and potentiated with supplementation. Exercise is a prerequisite.
Mitochondrial Supplements Detail
Nicotinamide Mononucleotinde (NMN)
Niacin and its metabolite nicotinamide mononucleotinde (
Niacin causes flushing (from prostaglandin activation) and blunts the release of free fatty acids (FFA). The flushing is uncomfortable but harmless, and reduced FFA release raises HDL. NMN does not have these effects. [Kamanna]
When niacin is metabolized, it uses a methyl group. This can be offset by supplementation of a methyl donor, such as 200–400mg Sam-e, B vitamins, trimethylglycine (betaine), or choline. All of these methyl donors have positive effects. Sam-e, in particular, restores intracellular GSH stores, especially in mitochondria. [Ming]
“Niacin, after undergoing biochemical reactions in the mitochondria with nicotinamide, and tryptophan forms nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP). NAD and NADP are the active forms of niacin which, when reduced to NAD(H) and NADP(H) respectively, participates in catabolic redox reactions and are cofactors in anabolic redox reactions.” (sic) [Zhang][Whitson]
A 2019 study showed that supplemental NMN reduced levels of creatinine, a metabolic waste product. The mechanism of action is most likely improved kidney function as a direct action of NMN [Weiss]. Because overtraining and creatine supplementation can both raise creatinine levels, NMN is a perfect complement to creatine supplementation or any HIIT exercise regimen.
Pyrroloquinoline quinone (PQQ)
Pyrroloquinoline quinone (PQQ) is a naturally occurring coenzyme manufactured by bacteria, found in plants, and utilized by mammalian cells as an important nutritional growth factor. Because humans do not produce PQQ, this necessary nutrient must be ingested, either from scant amounts found in food, or via supplementation.
PQQ stimulates mitochondrial biogenesis through cAMP response element-binding protein (CREB) phosphorylation and increased PGC-1 alpha expression. [Chowanadisai]
PQQ also protects against exercise-induced fatigue and oxidative damage by improving mitochondrial function. [Liu]
In a 2020 study out of Texas, a small group of untrained men were split into groups. One group got 20mg PQQ per day, the other group got a placebo, and both groups trained on a stationary cycle.
The PQQ group showed greater weight loss and improved mitochondrial biogenesis by way of significant elevations in PGC-1a protein content. Although no advantageous improvement in aerobic exercise performance was found in the PQQ group, the authors attribute this lack of observed aerobic performance to the test itself; that fatigue kicked in before VO₂ max could be realized. Regardless, the weight loss demonstrated that PQQ, even when used alone, has observable effects. [Hwang]
In a 2016 study out of Japan, just 20 mg of BioPQQ™ per day improved cognitive function of elderly subjects. [Itoh]
PQQ was tested with no-observed-adverse-effect-level (NOAEL) at 100 mg/kg bw per day in a 90-day repeated dose oral toxicity study with BioPQQ™. (For a 50kg (110lbs) person, that comes to 5000mg PQQ).
Coenzyme Q10 (CoQ₁₀)
Coenzyme Q10 (CoQ₁₀) is used in the electron transport chain to generate energy in the form of ATP from metabolic products (sugars, fats, and proteins). CoQ₁₀ protects mitochondria from oxidative damage and dysfunction.
CoQ₁₀ administration increases brain mitochondrial concentrations and exerts neuroprotective effects. CoQ₁₀ and PQQ work synergistically with 5-Amino-1MQ to improve neurological function and increase energy turnover. [Matthews][Sarmiento]
Ubiquinol, the reduced form of CoQ₁₀, has shown superior uptake to ubiquinone. Because ubiquinol is fat soluble, it should be taken with fat. [Zhang, Ying]
Phytosome Q10, a lipid-soluble form of CoQ₁₀, has demonstrated higher bioavailability and increased mitochondrial functionality in cultured cells. [Rizzardi
Creatine Monohydrate
Creatine increases power output by increasing ATP. ATP is used a few ways in energy production, including the citric acid cycle and the electron transport chain, both of which occur inside the mitochondria. [Cooper] (See also: How the mitochondria produces ATP in steps.)
Creatine protects mitochondria from damage, increases mitochondrial DNA (mtDNA), and induces mitochondrial biogenesis. This explains why creatine has been evidenced to fight the effects of aging. [Gowayed][Barbieri][Candow]
Coleus Forskolin
Coleus Forskolin activates the cAMP pathway inducing mitochondrial biogenesis, and increasing mtDNA and activity. [Bogacka]
Racemic Alpha-Lipoic Acid (r-ALA)
Alpha-Lipoic Acid (ALA) reduces mitochondrial dysfunction and oxidative damage. ALA protects cells, including neurons, from damage, and induces mitochondrial biogenesis. [Shen][Nutritionreview.org][Fernández-Galilea][Shay]
Sodium r-Lipoate (Na-r-ALA), the Best Form of ALA
Racemic ALA, or r-ALA, is the reduced form of ALA. r-ALA has shown significantly higher absorption than the synthetic S- form (s-ALA). Most commercial formulations use a combination of s- and r- enantiometers because it is cheaper to do so, but do not specify this. [Streeper]
Sodium r-Lipoate (Na-r-ALA) is less prone to polymerization (“gunking up”), is completely soluble in water, and displays much better absorption. [Carlson] Always use Na-r-ALA.
Acetyl L-Carnitine (ALCAR)
Carnitine directly affects mitochondrial respiration. It transfers activated long chain fatty acids into the mitochondria in a series of reactions called the “carnitine shuttle”. [Ferreira]
Carnitine spares glycogen and burns fat during exercise. The form Acetyl L-Carnitine (ALCAR) has the advantage of crossing the blood-brain barrier to reach the brain and improve neurological health and function. [Wall]
References
- [Chistiakov] The role of mitochondrial dysfunction in cardiovascular disease: a brief review
- [Jang] The role of mitochondria in aging
- [Liang] PGC-1 alpha: a key regulator of energy metabolism
- [Cantó] PGC-1α, SIRT1 and AMPK, an energy sensing network that controls energy expenditure
- [Park] Exercise training improves vascular mitochondrial function
- [Steiner] Exercise training increases mitochondrial biogenesis in the brain
- [Bishop] High-Intensity Exercise and Mitochondrial Biogenesis: Current Controversies and Future Research Directions
- [Granata] Forty high-intensity interval training sessions blunt exercise-induced changes in the nuclear protein content of PGC-1α and p53 in human skeletal muscle
- [Chung] The effects of exercise and cold exposure on mitochondrial biogenesis in skeletal muscle and white adipose tissue
- [Real-Hohn] The synergism of high-intensity intermittent exercise and every-other-day intermittent fasting regimen on energy metabolism adaptations includes hexokinase activity and mitochondrial efficiency
- [Anton] Flipping the Metabolic Switch: Understanding and Applying Health Benefits of Fasting
- [Silveira] Effects of photobiomodulation on mitochondria of brain, muscle, and C6 astroglioma cells
- [Eells] Mitochondrial signal transduction in accelerated wound and retinal healing by near-infrared light therapy
- [Keszler] Far red/near infrared light-induced protection against cardiac ischemia and reperfusion injury remains intact under diabetic conditions and is independent of nitric oxide synthase
- [Leal-Junior] Mitochondrial Bioenergetic, Photobiomodulation and Trigeminal Branches Nerve Damage, What’s the Connection? A Review
- [Walden] Acute endurance exercise stimulates circulating levels of mitochondrial-derived peptides in humans
- [Sarmiento] Coenzyme Q10 Supplementation and Exercise in Healthy Humans: A Systematic Review
- [Ravera] Mitochondrial Bioenergetic, Photobiomodulation and Trigeminal Branches Nerve Damage, What’s the Connection? A Review
- [Ferraresi] Low-level laser (light) therapy increases mitochondrial membrane potential and ATP synthesis in C2C12 myotubes with a peak response at 3-6 hours
- [Neelakantan 1] Small molecule nicotinamide N-methyltransferase inhibitor activates senescent muscle stem cells and improves regenerative capacity of aged skeletal muscle
- [Neelakantan 2] Selective and membrane-permeable small molecule inhibitors of nicotinamide N-methyltransferase reverse high fat diet-induced obesity in mice
- [Yang] MOTS-c interacts synergistically with exercise intervention to regulate PGC-1α expression, attenuate insulin resistance and enhance glucose metabolism in mice via AMPK signaling pathway
- [Campbell] Improving mitochondrial function with SS-31 reverses age-related redox stress and improves exercise tolerance in aged mice
- [Siegel] Mitochondrial targeted peptide rapidly improves mitochondrial energetics and skeletal muscle performance in aged mice
- [Zhang] Short-term administration of Nicotinamide Mononucleotide preserves cardiac mitochondrial homeostasis and prevents heart failure
- [Whitson] SS‐31 and NMN: Two paths to improve metabolism and function in aged hearts
- [Kamanna] The mechanism and mitigation of niacin-induced flushing
- [Kamanna] Synergistic protection by S-adenosylmethionine with vitamins C and E on liver injury induced by thioacetamide in rats
- [Matthews] Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects
- [Zhang, Ying] Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects
- [Rizzardi] Coenzyme Q10 Phytosome Formulation Improves CoQ10 Bioavailability and Mitochondrial Functionality in Cultured Cells
- [Chowanadisai] Pyrroloquinoline Quinone Stimulates Mitochondrial Biogenesis through cAMP Response Element-binding Protein Phosphorylation and Increased PGC-1α Expression
- [Liu] Pyrroloquinoline quinone protects against exercise-induced fatigue and oxidative damage via improving mitochondrial function in mice
- [Hwang] Effects of Pyrroloquinoline Quinone (PQQ) Supplementation on Aerobic Exercise Performance and Indices of Mitochondrial Biogenesis in Untrained Men
- [Itoh] Effect of the Antioxidant Supplement Pyrroloquinoline Quinone Disodium Salt (BioPQQ™) on Cognitive Functions
- [Shay] Alpha-lipoic acid as a dietary supplement: Molecular mechanisms and therapeutic potential
- [Streeper] Differential effects of lipoic acid stereoisomers on glucose metabolism in insulin-resistant skeletal muscle
- [Carlson] The plasma pharmacokinetics of R-(+)-lipoic acid administered as sodium R-(+)-lipoate to healthy human subjects
- [Ferreira] Chronic oral ingestion of l-carnitine and carbohydrate increases muscle carnitine content and alters muscle fuel metabolism during exercise in humans
- [Wall] L-Carnitine and acetyl-L-carnitine roles and neuroprotection in developing brain
- [Bogacka] Structural and functional consequences of mitochondrial biogenesis in human adipocytes in vitro
- [Irie]Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide¥ metabolite levels in healthy Japanese men
- [Weiss]Study Indicates NMN Has Anti-Aging Potential for Kidneys
- [Shen] R-alpha-lipoic acid and acetyl-L-carnitine complementarily promote mitochondrial biogenesis in murine 3T3-L1 adipocytes
- [NutritionReview.org] (R)-Lipoic Acid: Unique ‘Mitochondrial Antioxidant’ Fights Premature Aging
- [Fernández-Galilea] α-Lipoic acid treatment increases mitochondrial biogenesis and promotes beige adipose features in subcutaneous adipocytes from overweight/obese subjects
- [Barbieri] Creatine Prevents the Structural and Functional Damage to Mitochondria in Myogenic, Oxidatively Stressed C2C12 Cells and Restores Their Differentiation Capacity
- [Gowayed] Enhanced mitochondrial biogenesis is associated with the ameliorative action of creatine supplementation in rat soleus and cardiac muscles
- [Cooper] Creatine supplementation with specific view to exercise/sports performance: an update
- [Candow] Effectiveness of Creatine Supplementation on Aging Muscle and Bone: Focus on Falls Prevention and Inflammation
- [Rao] Lipid alterations in transient forebrain ischemia: possible new mechanisms of CDP-choline neuroprotection
Ginger & Capsaicin